Apparatus for performing haemostasis tests

ABSTRACT

The invention relates to a device for measuring coagulation parameters in a sample fluid, comprising an interface sensor with a sensor surface that faces the sample fluid. The invention is characterized in that said sensor surface includes adhesive areas and non-adhesive areas with respect to blood components.

This application is the national phase entry of PCT/EP2010/005534. Thisapplication claims the benefit and priority of and to PCT/EP2010/005534,international application filing date Sep. 9, 2010, which claims thebenefit and priority of and to German patent application no. DE 10 2009040 880.0, filed Sep. 9, 2009. Further, PCT/EP2010/005534 and Germanpatent application no. DE 10 2009 040 880.0 are hereby incorporatedherein by reference hereto.

The analysis of blood is of vital importance in medicine. It allows thedetection of various diseases, anomalies, infections or coagulationdisorders. Such analyses are generally performed on samples which werefirst taken from a blood stream and then further processed in alaboratory. Haemostasis analysis plays a special part here. Devices arealready widely used which allow a patient to directly determine acertain coagulation value. This is mainly true for Quick's value, theprothrombin time. However, for analysing different parameters, separatedevices have so far been required.

Furthermore, devices have been known that determine a substancecharacteristic by means of a vibrating quartz crystal. This technologyis widely known as “Quartz Crystal Microbalance” (QCM), as disclosed forexample in DE 696 101 83 T2. One aspect of QCM is based on the fact thatthe desired substances will adsorb to the specifically adhesive surfaceof the quartz crystal, thus changing its resonance frequency which inturn allows a conclusion to be drawn regarding the number or thefunctionality of the substances. Furthermore, quartz crystals have beendisclosed in WO 99 403 97 which comprise several oscillators and exhibitdifferent coatings for the detection of different substances.

Coagulation measurement using a resonator or a vibrating quartz crystalaccording to the prior art is rather inaccurate. For example, aviscosity measurement will not be possible if a viscoelastic layer isformed on a surface which has acoustically impermeable properties. Thisis the case, for example, if this layer is too thick for the penetrationdepth of the acoustic wave, thus preventing the acoustic wave fromreaching the sample fluid to be measured.

On the other hand, there is the additional problem that in a completelyprotein- and/or cell-resistant surface, coagulation will not directlytake place on the vibrating quartz crystal surface. As a result, theacoustic waves will not be able to penetrate deeply enough into themedium to be measured. In this case, the viscosity change brought aboutby coagulation cannot be measured at all or will not yield validmeasurements. Thus, while it is generally known to measure bloodparameters using a vibrating quartz crystal or a thickness-shearvibrator with a surface that faces the blood sample, the resultsobtained may not necessarily be reproducible, however.

It is the object of the invention to provide an apparatus for measuringhaemostasis which allows a reliable, precise and fast determination ofvarious primary and secondary haemostasis parameters.

The apparatus according to the invention for measuring haemostasisparameters comprises an interface sensor having a sensor surface whichconsists of both adhesive and non-adhesive areas with respect to bloodcomponents.

The combination of adhesive and non-adhesive areas of the resonatorsurface has the advantage that blood components of a sample fluid willmerely bind to the adhesive areas and bridge the non-adhesive areas byforming aggregates and fibrin meshes.

This reliably ensures that coagulation will take place directly on thesensor surface and that the viscosity change in the acousticallyimpermeable protein- and/or cell-resistant areas brought about bycoagulation will result in a useful sensor signal. Moreover, thisensures reliable and precise measurement of haemostasis parameters. Inaddition, the fact that the blood components can only bind to certainareas will ensure that the thicknesses of the layers created on thesensor surface will be smaller than the penetration depth of theinterface sensor.

For the sake of brevity, we will refrain from describing the excitationby an oscillator module and the specific type of vibration measurementused here. Vibrational excitation and measurement are known prior artand do not contribute to the concept of the present invention but merelyprovide the framework conditions.

In yet another advantageous embodiment, the non-adhesive areas are madeto be protein- and/or cell-resistant. This has the advantage that bloodcomponents will not adsorb to these surface areas. When there is anexcessive amount of blood components adhering to the surface, validmeasurement of a viscosity change will no longer be possible since theviscosity will be masked by the adhesion and/or the layer will beacoustically impermeable.

In yet another particularly advantageous embodiment, the adhesive andnon-adhesive areas are arranged in the shape of a mosaic on the surfaceof the vibrating quartz crystal. Such a surface design allowsparticularly precise measurements to be performed. Such a subdivisioninto different areas ensures optimal distribution of the anchoring siteswhich promotes the formation of a largely homogeneous layer.

In particular, the adhesive areas are made of gold and the non-adhesiveareas are made of poly ethylene (PE). Using these materials for thesurface areas is advantageous in that both gold and poly ethylene (PE)are widely used in microsystems engineering and thus well known and easyto process. Another advantage of the use of a gold layer is that it maysimultaneously serve as an electrode of the vibrating quartz crystal.

In particular, the surface of the vibrating quartz crystal is subdividedsuch that the non-adhesive areas occupy between at least 20 per cent andmaximally 90 per cent of the total sensor surface. This range will yieldthe best results.

Preferably, an activator such as thrombin has already been incorporatedinto the sensor surface. This avoids the problem of having to keep thetime period from sample activation to the actual measurement especiallyshort. For this reason, the entire apparatus can be of a simpler design.The activator may be applied both to the adhesive areas and thenon-adhesive areas.

The blood components will become activated as they adhere to thefibrinogen layer, which will then trigger aggregation. This will allowthe determination of the coagulation time, for example, from the timewhen the blood was applied until the actual coagulation.

In a particularly advantageous embodiment, the interface sensor isprovided in the form of an acoustic resonator. Alternatively, theresonator may take the form of a thickness-shear vibrator, a quartzcrystal microbalance or a vibrating quartz crystal. These forms arewidely used and well known in analytics.

According to an advantageous further development, the resonator surfacemay also include multiple layers. This is above all advisable for morecomplex coating processes.

In yet another embodiment, the interface sensor takes the form of anoptical sensor, in particular for surface plasmon resonance measurement.

Further advantages, features and possible applications of the presentinvention will become obvious from the description which follows, incombination with the embodiment illustrated in the drawings. Theinvention will now be described in more detail with reference to thesingle drawing. Throughout the description, the claims, the abstract andthe drawing, those terms and reference numerals will be used as arelisted in the list of reference numerals below. The sole FIGURE of thedrawing,

FIG. 1 is an illustration of a vibrating quartz crystal surfaceconsisting of PE and gold.

FIG. 1 shows the surface of a vibrating quartz crystal 10 which exhibitsa PE layer 12 and a gold layer 14. In a known manner, the PE layer hasbeen made to be cell-resistant. It thus prevents the adsorption ofproteins and other cell components and blood components 16. The goldlayer 14 by contrast is adhesive and thus allows blood componentsadsorption in this area. The blood components bridge the non-adhesive PEareas. The fact that only a small number of adsorption sites exist willensure a thickness of the blood components layer which allowssufficiently deep acoustic penetration. Furthermore, as a result of theanchoring sites formed, the coagulation process will be triggered nearthe surface of the vibrating quartz crystal.

Thus it will not be only possible to measure plasmatic coagulationparameters but to also determine platelet function. As a result, it canbe determined which coagulation branch is defective.

LIST OF REFERENCE SIGNS

10 vibrating quartz crystal

12 PE layer

14 gold layer

16 blood components

1-12. (canceled)
 13. An apparatus for measuring coagulation parametersin a sample fluid, comprising: an interface sensor (10), said interfacesensor includes a sensor surface, said sensor surface faces said samplefluid; said sample fluid includes blood components; said sensor surfaceincludes adhesive areas (14), said adhesive areas are adhesive withrespect to blood components; and, said sensor surface includesnon-adhesive areas (12), said non-adhesive areas are non-adhesive withrespect to blood components.
 14. The apparatus of claim 13 characterizedin that said non-adhesive areas (12) of said sensor surface are made tobe as protein resistant and/or cell resistant as possible.
 15. Theapparatus of claim 13 characterized in that said adhesive areas (14) ofsaid sensor surface and said non-adhesive areas (12) of said sensorsurface are arranged in a mosaic on said sensor surface.
 16. Theapparatus of claim 13 characterized in that said non-adhesive areas ofsaid sensor surface are made of polymer coatings, in particularpolyethylene or polyethylene glycol.
 17. The apparatus of claim 13characterized in that said adhesive areas (14) of said sensor surfaceare made of gold or polystyrene.
 18. The apparatus of claim 13characterized in that said non-adhesive areas of said sensor surfaceoccupy between at least 20% and maximally 90% of the total surface. 19.The apparatus of claim 13 characterized in that one activator has beenincorporated into said sensor surface.
 20. The apparatus of claim 19characterized in that said sensor surface includes fibrinogen.
 21. Theapparatus of claim 20 characterized in that said sensor surface includesmultiple layers.
 22. The apparatus of claim 13 characterized in thatsaid interface sensor is provided in the form of a resonator.
 23. Theapparatus of claim 22 characterized in that said resonator is in theform of an acoustic resonator, in particular in the form of a vibratingquartz crystal or a thickness-shear vibrator.
 24. The apparatus of claim13 characterized in that said interface sensor is provided in the formof an optical sensor, in particular for surface plasmon resonancemeasurement.
 25. The apparatus of claim 14 characterized in that saidinterface sensor is provided in the form of a resonator.
 26. Theapparatus of claim 15 characterized in that said interface sensor isprovided in the form of a resonator.
 27. The apparatus of claim 16characterized in that said interface sensor is provided in the form of aresonator.
 28. The apparatus of claim 25 characterized in that saidresonator is in the form of an acoustic resonator, in particular in theform of a vibrating quartz crystal or a thickness-shear vibrator. 29.The apparatus of claim 26 characterized in that said resonator is in theform of an acoustic resonator, in particular in the form of a vibratingquartz crystal or a thickness-shear vibrator.
 30. The apparatus of claim27 characterized in that said resonator is in the form of an acousticresonator, in particular in the form of a vibrating quartz crystal or athickness-shear vibrator.
 31. The apparatus of claim 14 characterized inthat said interface sensor is provided in the form of an optical sensor,in particular for surface plasmon resonance measurement.
 32. Theapparatus of claim 15 characterized in that said interface sensor isprovided in the form of an optical sensor, in particular for surfaceplasmon resonance measurement.